Date of Award

2021

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Abstract

The rising antimicrobial resistance to antibiotics is a major global problem, which has been exacerbated by the inappropriate use of antibiotics. The effectiveness of frequently prescribed penicillin derivatives and β-lactamase inhibitors are compromised by the evolution of bacterial β-lactamases and antibiotic-resistant bacteria. Consequently, design and synthesis of small-molecule inhibitors of identified novel antibiotic targets is an urgent unmet medical need. We previously demonstrated that N-functionalized α-aminocyclobutanones can act as peptidomimetic enzyme inhibitors, including inhibition of a key esterase in Francisella Tularensis. The carbonyl of a cyclobutanone is electrophilic due to ring strain, therefore cyclobutanone derivatives can serve as transition state inhibitors of serine- and metallo-β-lactamases, serine proteases, and other metalloenzymes including DapE. The bacterial enzyme N-succinyl-L,L-diaminopimelic acid desuccinylase (DapE) is a novel antimicrobial target and a key enzyme in the bacterial lysine biosynthetic pathway. DapE catalyzes the hydrolysis of N-succinyl-L,L-diaminopimelic acid (L,L-SDAP) to succinate and L,L-diaminopimelic acid (L,L-DAP) and the products of this reaction are critical precursors of bacterial cell wall synthesis. Due to the absence of the lysine biosynthetic pathway in mammals, inhibitors of DapE should be free of mechanism-based toxicity in humans which makes DapE a promising antibiotic drug target. I have developed an efficient synthetic route to make 2-aminocyclobutanone derivatives via a modular synthon and employed this methodology to synthesize a library of N-functionalized 2-aminocyclobutanone derivatives. The cyclobutanone library was tested against DapE using our ninhydrin assay, and a number of these analogs showed promising inhibition of DapE with IC50s less than 100 µM. This library has also provided inhibitory potency of the coronavirus main protease (3CLpro) and demonstrated efficacy against SARS-CoV-2 in vitro. Following up on other DapE inhibitors that were identified through a high-throughput-screen, tetrazole-based inhibitors have been synthesized and are being tested as inhibitors of DapE.

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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